N-alkylsulfinylalkyl- and sulfonylalkyl-1,2,3,4-tetrahydroisoquinolines



United States Patent 3,549,640 N-ALKYLSULFINYLALKYL- AND SULFONYLAL-KYL-l,2,3,4-TETRAHYDROISOQUINOLINES Allan Poe Gray, Bedford Village,N.Y., assignor, by mesne assignments, to Mallinckrodt Chemical Works,St.

Louis, Mo., a corporation of Missouri No Drawing. Filed Nov. 3, 1967,Ser. No. 680,354 Int. Cl. C07d 35/42 US. Cl. 260-283 8 Claims ABSTRACTOF THE DISCLOSURE N-sub stituted 1,2,3,4-tetrahydroisoquinolinesexemplified by 2-(3-ethylsulfinylpropyl)-1,2,3,4-tetrahydroisoquinoline.

exert cardiovascular effects when administered as their hydrochlorides.Such sulfinyl compounds are prepared by oxidation of the correspondingthio others, which may also be oxidized to the corresponding sulfonylcompounds. Substitution on the aromatic and heterocyclic rings andvariations in the side chain are disclosed.

This invention relates to compositions of matter classified in the artof chemistry as tetrahydroisoquinolines having an aliphaticsulfur-containing substitutent attached to the ring nitrogen atom.

The invention sought to be patented in its composition aspect, isdescribed as residing in the concept of a chemical compound having thegeneralized structure:

Billn R! I N-AX-R Hfl-n) wherein A contains up to 7 carbon atoms and isselected from the group consisting of alkylene; alkenylene;alkyleneoxycarbonyl; or alkyleneamino; X is selected from the groupconsisting of thio, sulfinyl or sulfonyl; R contains up to 7 carbonatoms and is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, alkaryl, arakyl, amino,aminoalkyl, alkylamino, dialkylamino, alkylaminoalkyl,dialkylaminoalkyl, amidino, aminothiocarbonyl, alkylthiocarbonyl, cyanoor akylsulfonyl; R represents a member selected from the groupconsisting of hydrogen or alkyl; and R" represents a member selectedfrom the group consisting of lower alkyl, lower alkoxy, aminoalkyl,lower dialkylamino, acetamino, halo, e.g., chloro, bromo, fiuoro, iodo;haloalkyl, e.g., chloromethyl, trifiuoromethyl; or methylenedioxy, i.e.two Rs form OCH O- wherein the oxygen atoms are attached to the aromaticring at adjacent positions, and n has a value of from zero to 2.

As used herein, the term lower alkyl" means alkyl radicals having 1 to 4carbon atoms, inclusive, either straight or branched chain, among whichare, for purposes of illustration, but without limiting the generalityof the foregoing, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl,"secondary-butyl, and tertiary-butyl.

Preferred compositions encompassed by this invention are thoserepresented by the aforementioned formula wherein A contains from 2 to 6carbon atoms and R, R and R" each contain up to 7 carbon atoms. Alsopreferred compositions are those wherein R and R" represents hydrogen, Xrepresents thio, sulfinyl, or sulfonyl, A represents an alkylene groupand R represents alkyl. Particularly preferred compositions are thosewherein the ring nitro'gen and the sulfur atoms are separated by atleast 3 carbon atoms, i.e. A has at least 3 unbranched carbon atoms, andthe total number of carbon atoms in A and R is from 5 to 7.

The invention sought to be patented in the process of preparationaspects is described as residing in the concept of embodying such amolecular structure in tangible form by linking a sulfur-containingorganic moiety and a tetrahydroisoquinoline throulgh its nitrogen atomby one or more processes. For example the compositions can be formed by(1) the reaction of a 2-(haloalkyl)-1,2,3,4- tetrahydroisoquinoline witha thiol to give a 2-(thioalky1)- l,2,3,4-tetrahydroisoquinoline (2)oxidizing the Z-(thioalkyl)-1,2,3,4-tetrahydroisoquinoline to a2-(su1finy1- alkyl)-1,2,3,4-tetrahydroisoquinoline, or (3) oxidizing theZ-(thioalkyl)-1,2,3,4-tetrahydroisoquinoline to the corresponding 2-(sulfonylalkyl) 1,2,3 ,4-tetrahydroisoquinoline.

The invention sought to be patented, in the process of using aspect, isdescribed as residing in the concept of using the tangible embodiment ofa composition of matter identified as a tetrahydroisoquinoline with asulfur-containing substituent on the nitrogen atom by administering towarm blooded animals such composition as the essential active ingredientof a pharmaceutical formulation. It has been observed that the tangibleembodiments of the invention possess the inherent applied usecharacteristics of increasing blood pressure and producing favorablecardiovascular effects as hereinafter evidenced by clinical evaluation.In addition to increasing blood pressure, the novel compositions of thisinvention'have also been found to have vasodilator activity.

The tangible embodiments of the composition aspect of the invention intheir free base form are, for the most part, liquids having low aqueoussolubility and are soluble in polar solvents such as lower aliphaticalcohols. Examination of the compounds produced according to the hereindescribed process reveals physical characteristics such as infraredspectra which confirm the molecular structure hereinbefore set forth.The aforementioned physical characteristics, taken together withanalytical data the nature of the starting materials and the mode ofsynthesis positively confirm the structure of the compositions sought tobe patented.

It will be apparent from the definition of A--X-R in the aforementionedformula that it is intended to include specifically or as equivalents,such representative radicals as the thioalkyl groups, e.g.,methylthiomethyl,

3 methylthiopropyl, ethylthiopropyl, propylthiopropyl,methylthioisopropyl, butylthiopropyl, cyclohexylthiobutyl,cyclohexylthioisobutyl, phenylthiopropyl, naphthylthiopropyl, and thelike.

Other representative radicals include the aminoalkylthioalkyl groups,e.g., aminomethylthiopropyl, aminopropylthiopropyl,methyl'aminoethylthiopropyl, dimethylaminopropylthiopropyl,diethylaminopropylthiopropyl, and the like; the amidinothioalkyl groups,e.g., amidino thiopropyl, amidinothiobutyl, and the like; thethiocyanoalkyl groups, e.g., thiocyanoethyl, thiocyanopropyl,thiocyanobutyl, thiocyanopentyl, thiocyanoisobutyl, and the like.

Further representative radicals included within the aforementionedformula are thioformoxyalkyl groups, e.g., ethylthiofromoxyethyl,propylthioformoxyethyl, propylthioformoxypropyl, benzylthioformoxybutyl,benzylthioformoxypentyl, and the like; the thiocarbamylthioalkyl groups,e.g., thiocarbamylthioethyl, thiocarbamylthiopropyl,thiocarbamylthioisobutyl, and the like; the alkylcarbonyldithio'alkylgroups, e.g., ethylcarbonyldithioethyl, and the like; thealkylsulfonylthioalkyl, e.g., ethylsulfonyl thioethyl, and the like.

Additional representative radicals include the alkylsulfinylalkylgroups, e.g., ethylsulfinylpropyl, propylsulfinylpropyl,methylsulfinylethyl, propylsulfinylethyl, and the like.

Further representative groups include the alkylsulfonylalkyl groups,e.g., ethylsulfonylpropyl, propylsulfonylpropyl, methylsulfonylethyl,and the like. Also included are the sulf'amidoalkyl groups, e.g.,sulfamidoethyl, sulfamidopropyl, and the like; thedialkylsulfamidoalkyl, e.g., N,N-dimethylsulfamidoethyl, and the like.

Synthesis of the novel tetrahydroisoquinolines of the present inventionmay be effected by a variety of processes as hereinafter indicated inthe examples. For instance, the 2-(alkylthioalkyl) 1,2,3,4tetrahydroisoquinolines are prepared by refluxing the appropriatealkylthioalkyl halide with tetrahydroisoquinoline. Alternatively, a2-(haloalkyl)-tetrahydroisoquinoline hydrochloride can be prepared andthen reacted with the appropriate alkylthiol in the presence of an acidacceptor. The sulfinyl and sulfonyl derivatives are prepared byoxidation of the corresponding thio compound. The generalized processesfor the preparation of the thio compositions can be illustrated asfollows:

nil RI Rlln R! j YA-SR NH NASR R.. R R"n X11 I RSH I NA-Y \/NASR it-n)G-fl) wherein A, n, R, R and R" are as previously defined and Yrepresents halogen, e.g., chloro, bromo, iodo, or R -SO wherein R" islower alkyl or aryl.

Thereafter, the thio composition (1) is oxidized to the correspondingsulfinyl or sulfonyl derivative.

In the above described synthesis, it will be apparent to those skilledin the art of chemistry that the proportion of reactants, duration ofreaction, solvents, acid acceptors, catalysts and the like can be varieddepending on the type of reactant.

From the specific reaction conditions given in the examples, it will beobvious to those skilled in the art of chemistry that the reagents andconditions which can be employed in the inventive process will depend toa great extent on the nature of the thiol as well as the particulartetrahydroisoquinoline.

In general, a temperature range from about 0 C. to about the refluxtemperature of the solvent has been found to be satisfactory.Temperatures above and below the aforementioned range can also beemployed but are less preferred. A preferred range is from about 25 C.to about 150 C.

It is also preferred, although not necessary, that the reaction of thetetrahydroisoquinoline and thiol compound be conducted in an inertsolvent. In general, the choice of solvent will largely be dependentupon its inability to undergo reactions with either the startingmaterials or reaction products, its ease of separation from the reactionproduct, as well as economic considerations.

A variety of inert solvents can be employed in the practice of theinstant process, i.e., saturated aliphatic hydrocarbons, aromatichydrocarbons, aliphatic alcohols, and the like. Typical solvents whichcan be employed include benzene, toluene, xylene, ethanol, tertiarybutanol, secondary butanol, 2-propanol, tertiary amyl alcohol, methylisobutyl carbinol, acetone, acetonitrile, dimethylformamide, and thelike. Preferred solvents are those completely miscible with thereactants and which can be readily separated.

Pressure is not necessarily critical and the process can be conducted atatmospheric, subatmospheric or superatmospheric pressures.

The contact time necessary to effect the novel process of the presentinvention need only be of such duration as to insure optimum conversionof the reactants to the corresponding 2-substitutedtetrahydroisoquinoline compound. Reaction times of several hours arethoroughly practicable. Shorter or longer periods can also be feasiblyemployed depending upon the temperature (higher temperatures usuallypermit the use of shorter reaction times), and the manner in which theprocess is conducted.

Oxidation of the 2-(aliphaticthioalkyl)-l,2,3,4-tetrahydroisoquinolineto the corresponding sulfinyl or sulfonyl compounds can be convenientlyeffected by known prior art procedures. For example,2-(3-ethylthiopropyl)-1,2, 3,4-tetrahydroisoquinoline can be oxidizedeasily to 2-(3- ethylsulfinylpropyl)1,2,3,4 tetrahydroisoquinoline withperacetic acid. Other peroxides can also be employed.

Preparation of the2-(alkylsulfonylalkyl)-1,2,3,4-tetrahydroisoquinolines are likewiseprepared by the oxidation of theZ-(alkylthioalkyl)-1,2,3,4-tetrahydroisoquinolines with an appropriateoxidizing agent such as hydrogen peroxide and the like.

As previously indicated, the starting materials for the preparation ofthe novel composition of this invention are the tetrahydroisoquinolinesand the thiols. These reactants are known compounds or can be preparedby the methods indicated in the examples.

The manner of making and using the compositions and processes of theinvention is further illustrated by the following examples, which setforth one mode contemplated for carrying out the invention so as toenable any person skilled in the art of chemistry to make and use thesame.

EXAMPLE 1 2- (S-methylthiopropyl) -1,2,3 ,4-tetrahydroisoquinoline Asolution of 16.2 g. (0.13 mole) of 3-methylthiopropyl chloride and 34.6g. (0.26 mole) of tetrahydroisoquinoline in 100 ml. of benzene washeated at reflux on a steam bath for hours during which a crystallineprecipitate slowly formed. The precipitate was filtered off(tetrahydroisoquinoline hydrochloride, 14.7 g., 67% yield) and thefiltrate was concentrated in vacuo. Distillation and redistillation ofthe residue afforded 11.5 g. (40%) of 2-(3\methylthiopropyl)-1,2,3,4-tetrahydroisoquinoline as a yellow oil, B.P.138-140" (0.5 mm.), n 1.5608.

Analysis.-Calcd. for C H NS (percent): N, 6.33. Found (percent):N(basic), 6.14.

Treatment of an ether solution of the base with ethereal hydrogenchloride and recrystallization from ethanol gave 2- (3-methylthiopropyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride in the form of small,colorless needles, M.P. 184-186".

Analysis.Calcd. for C H ClNS (percent): C, 60.56; H, 7.82; CI 13.75.Found (percent): C, 60.14; H, 7.73; Cl(ionic), 13.78.

EXAMPLE 2 2-(3-ethylthiopropyl)-1,2,3,4-tetrahydroisoquinoline (A) Asolution of 215 g. (1.6 moles) tetrahydroisoquinoline and 126 g. (0.8mole) of trimethylene chlorobromide in 1300 m1. of benzene was stirredat room temperature for 100 hours. The precipitate of 130 g. oftetrahydroisoquinoline hydrobromide was filtered off and the filtratewas extracted with dilute hydrochloric acid. The aqueous extract wasmade alkaline with solid potassium carbonate and the precipitated oiltaken into ether. Drying and removal of the ether and distillation ofthe residue yielded 89 g. (53%) of 2-(3-chloropropyl)-tetrahydroisoquinoline, B.P. 131137 (3 mm.), 21 1.5463.

Analysis.Calcd. for C H ClN (percent): N,6.6'8. Found (percent):N(basic), 6.63.

2-(3-chloropropyl) tetrahydroisoquinoline hydrochloride, prepared inether and recrystallized from isopropyl alcohol-ether, showed M.P.187187.5.

Analysis.Calcd. for C H CI N (percent): C, 58.54; H, 6.96; Cl(ionic),14.40. Found (percent): C,58.27; H, 7.21; Cl(ionic), 14.40.

(B) To a cooled solution of 18.7 g. (0.81 g. atom) of metallic sodium in300 ml. of ethanol was added 29.9 g. (0.48 mole) of ethanethiol. Thesolution was allowed to come to room temperature and 79.3 g. (0.32 mole)of 2-(3-chloropropyl) tetrahydroisoquinoline hydrochloride dissolved in150 ml. of methanol was added dropwise with stirring over a period of 20minutes. A white precipitate formed during the addition. The reactionmixture was stirred at room temperature for 0.5 hour and at reflux forone hour. About 100 ml. of solvent was distilled out of the reactionmixture which was then poured into one liter of water and extracted withether. The ether solution was extracted with dilute hydrochloric acid. Ahydrochloride salt precipitate formed during the extraction. The aqueousmixture was made alkaline and extracted with ether. Drying and removalof the ether and distillation of the residual oil gave 61.5 g. (81%) of2-(3-ethyl-thiopropyl) 1,2,3,4 tetrahydroisoquinoline, B.P. 150-156 (0.4mm.), 11 1.5521.

Analysis.-Calcd. for C H NS (percent): N, 5.95. Found (percent):N(basic), 5.87.

2-(3-ethylthiopropyl) 1,2,3,4 tetrahydroisoquinoline hydrochloride,recrystallized from isopropyl alcohol, formed colorless plates, M.P.200.5-202.

Analysis.-Calcd. for C H ClNS (percent): C, 62.02; H,8.24; Cl, 13.04.Found (percent): C, 61.85; -H, 8.16; Cl(ionic), 13.00.

EXAMPLE 3 2-(3-ethylsulfinylpropyl)-1,2,3,4-tetrahydroisoquinoline To anice cold solution of 23.5 g. (0.1 mole) of the base produced in Example2B and 6 ml. of glacial acetic acid in 50 ml. of acetonitrile was added,dropwise with stirring, a solution of 19 g. of commercial 40% peraceticacid (0.1 mole) in 25 ml. of acetonitrile. The reaction mixture wasstirred at room temperature for a period of one hour, poured into 150ml. of water, made basic with dilute aqueous ammonia and extracted withether. The

ether solution was washed with a dilute potassium carbonate solution,water, dried and treated with ethereal hydrogen chloride. The resultantprecipitate was recrystal- -1ized from isopropyl alcohol to yield 13.4g. (47%) of 2-(3-ethylsulfinylpropyl) 1,2,3,4 tetrahydroisoquinolinehydrochloride in the form of colorless plates, M.P. 198- 199.

Analysis.Calcd. for C H 'ClNOS (percent): C, 58.41; H, 7.70; CI, 12.32.Found (percent): C, 58.53; H, 7.66; Cl(ionic), 12.35.

EXAMPLE 4 2- (3-ehy1sulf0nylpropyl) -1,2,3 ,4-tetrahydroisoquino1ine Toa solution of 23.5 g. (0.1 mole) of the base produced in Example 2B inml. of glacial acetic acid was added, dropwise with stirring andmaintenance of the temperature at about 30 by external cooling, 27.2 g.dt 50% hydrogen peroxide (0.4 mole). After the addition was complete,the solution was allowed to stand for 48 hours at room temperature,poured into 400 ml. of water, made basic and extracted with ether. Theether extract was shaken with dilute hydrochloric acid, the aqueous acidsolution was made basic and extracted with ether. The ether layer waswashed with water, dried over magnesium sulfate and treated withethereal hydrogen chloride. Recrystallization of the precipitate from amixture of isopropyl alcohol and ethanol afforded 13.6 g. (45%) of2-(3-ethylsulfonylpropyl)-1,2,3,4-tetrahydroisoquinoline hydrochloridein the form of colorless plates, M.P. 226228.

Analysis.-Calcd. for C H ClNO S (percent): C, 55.34; H, 7.30; Cl, 11.67.Found (percent): C, 55.13; H, 7.15; Cl(ionic), 11.78.

EXAMPLE 5 2- (3 -propylthiopropyl) 1 ,2,3,4-tetrahydroisoquino1ine To astirred, ice cold solution of 16.1 g. (0.7 g. atom) of metallic sodiumin 250 ml. of ethanol was added 31.2 g. (0.41 mole) of 1-propanethiol.The solution was allowed to come to room temperature and a solution of67.5 g. (0.27 mole) of the hydrochloride salt prepared in Example 2B inml. of methanol was added dropwise with stirring. Stirring was continuedand the reaction mixture was heated at reflux on a steam bath for 2.5hours. The reaction mixture was concentrated to about one-half itsoriginal volume, poured into 700 ml. of water and extracted with ether.The ether solution was extracted with dilute hydrochloric acid. Theaqueous acid solution was made basic with aqueous sodium hydroxide andextracted with ether. The ether was dried and evaporated and theresidual oil distilled to give 60.1 g. (90%) of2-(3-propylthiopropyl)-1,2,3,4-tetrahydroisoquinoline, B.P. -167 (0.2mm.).

Analysis.-Calcd. for C H NS (percent): N, 5.62. Found (percent):N(basic), 5.67.

2 (3 propylthiopropyl) 1,2,3,4 tetrahydroisoquinoline hydrochloride,recrystallized from isopropyl alcoholether, formed colorless plates,M.P. -197".

Analysis.-Calcd. for C H C1NS (percent): C, 63.02; H, 8.46; Cl, 12.40.Found (percent): C, 62.79; H, 8.49; Cl(Schtiniger), 12.51.

EXAMPLES 6-12 In the following examples the analogous compounds wereprepared as indicated. The methods employed were the same as those setforth for the preceding examples. The

precipitate of triethylamine hydrochloride (9.0 g., 94%) was filteredoff. Extraction of the filtrate with dilute hydrochloric acidprecipitated the crude hydrochloride salt of the product which wasrecrystallized from acetonitrileether to give 7.1 g. (36%) (a smallamount of additional material was obtained from the aqueous acid motherliquor) of 2 (ethylthiolformoxyethyl)-l,2,3,4-tetrahydroisoquinolinehydrochloride, M.P. 174-176".

Analysis.Calcd. for C H ClNO S (percent): C, 55.71; H, 6.68; CI, 11.75.Found (percent): C, 55.86; H, 6.62; Cl(Schiiniger), 11.85.

EXAMPLE 17 (1,2,3,4-tetrahydroisoquinolinoethyl)-isothiuronium chloridehydrochloride A mixture of 23.2 g. (0.1 mole) of2-chloroethyltetrahydroisoquinoline hydrochloride, 15.2 g. (0.2 mole) ofthiourea and 75 ml. of isopropyl alcohol was heated at reflux on a steambath for 30 hours. The precipitate was collected and recrystallized froma mixture of isopropyl alcohol and methanol to give 24.3 g. (79%) of(l,2,3,4- tetrahydroisoquinolinoethyl)-isothiuronium chloridehydrochloride, M.P. l88-1 89 Analysis.Calcd. for C H Cl N S (percent):C, 46.75; H, 6.21; Cl, 23.00. Found (percent): C, 46.84; H, 6.57;Cl(ionic), 22.93.

EXAMPLE 18 2- (thiocarbamylthioethyl) -1,2,3,4-tetrahydroisoquinoline Asolution of 20.3 g. (0.08 mole) of the hydrochloride salt of the productobtained in Example in 500 ml. of methanol was saturated with hydrogensulfide at room temperature and allowed to stand for 36 hours. Thereaction mixture was concentrated to dryness and the solid residue wastaken up in water, made basic with aqueous ammonia and extracted withether. The ether solution was dried over magnesium sulfate, treated withethereal hydrogen chloride, and the precipitate was recrystallized frommethanolether to yield 12.0 g. (52%) of 2-(thiocarbamylthioethyl)1,2,3,4 tetrahydroisoquinoline hydrochloride in the form of colorlessprisms, M.P. 195- 196.

Analysis.--Calcd. for C H ClN S (percent): S, 22.20; Cl, 12.27. Found(percent): S(Sch6niger), 22.69; Cl(Schtiniger), 12.37.

EXAMPLE 19 1,2,3,4-tetrahydroisoquinolinoethyl ethanethiosulfonate Amixture of 28.9 g. (0.176 mole) of potassium ethanethiosulfonate, thebase obtained from 53 g. (0.23 mole) of 2chloroethyltetrahydroisoquinoline hydrochloride, 300 ml. of acetone and20 ml. of water was stirred at room temperature for one hour and atreflux on a steam bath for five hours. The reaction mixture was filteredand the filtrate was concentrated to about one-third its volume andpoured into 400 ml. of water. The oil precipitate was taken into ether.The ether extract was shaken with dilute hydrochloric acid, and theprecipitate that formed was crystallized from methanol-ether to yield2.9 g. of 1,2,3,4- tetrahydroisoquinolinoethyl ethanethiosulfonatehydrochloride as colorless platelets, M.P. 199-200".

Analysis.Calcd. for C H ClNO S (percent): S, 19.93; Cl, 11.01. Found(percent): S(Sch6niger), 20.12; Cl(ionic), 11.38.

EXAMPLE 20 -2(ethylcarbonyldithioethyl)-1-1,2,3,4-tetrahydroisoquinoline (A) A slurry of 122 g. (0.396 mole) of theproduct obtained in Example 17 with 34 g. (0.85 mole) of sodiumhydroxide in 300 ml. of water was saturated with sodium chloride andextracted with ether. The ether solution was dried and concentrated toleave a clear oil which was distilled to yield 33.3 g. (43.5%) ofZ-mercaptoethyltetrahydroisoquinoline, B.P. (0.2 mm.), n 1.5780.

Analysis-Calcd. for C H NS (percent): N, 7.25. Found (percent):N(basic), 7.20..

2 mercaptoethyl 1,2,3,4 tetrahydroisoquinoline hydrochloride formedcolorless needles from ethanol, M.P. 21 8-220".

Analysis.-Calcd. for C H ClNS (percent): Cl, 15.43; S, 13.95. Found(percent): Cl(SchGniger), 15.86; S(Sch6niger), 13.90.

(B) A solution of 14.5 g. (0.064 mole) of the hydrochloride saltobtained in Example 20A and 5.1 g. (0.13 mole) of sodium hydroxide inml. of water was washed with ether and treated with 8.7 g. (0.07 mole)of ethyl chlorothiolformate. A light yelow oil precipitate formedrapidly. After being stirred at room temperature for 1.5 hours, thereaction mixture was extracted with ether. The ether solution was shakenwith dilute hydrochloric acid to precipitate a white solid which was recrystallized from acetonitrile-ether to yield 9.8 g. (48%) of 2(ethylcarbonyldithioethyl) 1,2,3,4-tetrahydroisoquinoline hydrochloride,M.P. l61.6162.4.

Analysis. Calcd. for C H CINOS (percent): C, 52.89; H, 6.34; C], 11.15;S, 20.17. Found (percent): C, 52.88; H, 6.5 8; Cl(Schiiniger), 10.96;S(Sch6niger), 20.44.

EXAMPLE 21 2-sulfamidoethyl-1,2,3,4-tetrahydroisoquinoline A mixture of8.8 g. (0.05 mole) of 2-aminoethyltetra hydroisoquinoline, 4.8 g. (0.05mole) of sulfamide and 5 ml. of water was heated at an oil bathtemperature of 120 for 4.5 hours at which time ammonia evolution ceased.The reaction mixture was extracted with chloroform and the chloroformextract was dried and concentrated to an amber oil. An isopropyl alcoholsolution of the oil was treated with ethereal hydrogen chloride and theprecipitate was recrystallized from a mixture of methanol, ethanol andether to yield 5.0 g. (40%) of 2-sulfamidoethyl-1,2,3,4tetrahydroisoquinoline hydrochloride as colorless plates, M.P.186187.

Analysis.-Calcd. for C H ClN O S (percent): C, 45.28; H, 6.22; Cl,12.15; S, 10.97. Found (percent): C, 45.82; H, 6.17; Cl(ionic), 12.27;S(Sch6niger), 10.81.

EXAMPLE 22 Z-dimethylsulfamidoethyl l ,2,3,4-tetrahydroisoquinoline To asolution of 7.9 g. (0.055 mole) of dimethylsulfamyl chloride in 100 ml.of anhydrous ether was added, dropwise with stirring at roomtemperature, 8.8 g. 0.05 mole) of Z-aminoethyltetrahydroisoquinoline asa white precipitate began to form. The reaction mixture was stirred atroom temperature for 20' hours and then at reflux for 7 hours. Theprecipitate of 2-aminoe'thyltetrahydroisoquinoline monohydrochloride wasfiltered off and the filtrate was concentrated to dryness. The residuewas heated on a. steam bath for 15 minutes, taken up in Water and theaqueous solution was washed with ether, made basic and extracted withether. Treatment of the dried ether extract with ethereal hydrogenchloride and repeated recrystallization of the precipitate fromisopropyl alcohol aflorded 4.0 g. (25%) ofZ-dimethylsulfamidoethyl)-l,2,3,4-tetrahydroisoqu inoline hydrochloridein the form of large colorless plates, M.P. l70'171.

Analysis-Calcd. for C H ClN O S: (percent): C, 48.81; H, 6.93; CI,11.08. Found (percent): C, 48.82; H, 6.72; Cl(ionic), 11.08.

1 1 EXAMPLE 23 2- 3 -ethylsulfonylpropyl -6-methyll ,2,3 ,4-tetrahydroisoquinoline In a manner similar to that set forth in Example2A 2 (3-chloropropyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline isprepared from the reaction of 6-methyltetrahydroisoquinoline 1.6 moles)and trimethylene chlorobromide (0.8 mole), thereafter the hydrochloridesalt is formed, recrystallized and dissolved in methanol. To a cooledsolution of 18.7 grams (0.81 g. atom) of metallic sodium in 300 ml. ofethanol is added 29.9 gram (0.48 mole) of ethanethiol. The solution isallowed to reach room temperature and the2-(chlorpropyl)-6-methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride(0.32 mole) dissolved in methanol is added dropwise. Thereafter thereaction mixture is stirred at reflux for about one hour. Afterdistilling off a portion of the solvent, the reaction mixture is pouredinto Water and extracted with ether. The ether solution is thenextracted with dilute HCl, the aqueous mixture made alkaline andextracted with ether. Drying and removal of the ether and distillationof the residue gives2-(3-ethylthiopropyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline. Elementaland infrared analysis confirms the structure.

To an ice cold solution of 0.1 mole of the2-(3-ethylthiopropyl)-6-methyl-l,2,3,4-tetrahydroisoquinoline and 6 ml.of glacial acetic acid in 50 ml. of acetonitrile is added, dropwise withstirring, a solution of 19 grams of commercial 40% peracetic acid (0.1mole) in milliliters of acetonitrile. The reaction mixture is stirred atroom temperature for one hour, poured into 150 ml. of water, made basicwith dilute aqueous ammonia and extracted with ether. The ether solutionis washed with dilute potassium carbonate solution, dried and treatedwith ethereal hydrogen chloride. The resulting precipitate isrecrystallized from isopropyl alcohol to yield2-(3-ethylsulfinylpropyl)- 6 methyl 1,2,3,4-tetrahydroisoquinolinehydrochloride. Elemental and infrared analysis confirms the structure.

EXAMPLES 24-31 In the following examples the analogous compounds areprepared as indicated. The methods employed are the same as those setforth in the preceding example. The starting materials and finalproducts are set forth in Table 11 below:

1.2; peripheral vascular system has been observed when thetetrahydroisoquinoline was administered.

Various well known procedures were carried out to ascertain thecardiovascular effect of2-(3-ethylsulfinylpropyl)-1,2,3,4-tetrahydroisoquinoline. In thepreliminary tests2-(3-ethylsulfonylpropyl)-l,2,3,4-tetrahydroisoquinoline wasadministered to anesthetized and unanesthetized dogs as thehydrochloride.

in the case of unanesthetized dogs, the systolic blood pressure wasmeasured indirectly by using a tail cuff technique with the pressurerecorded on a Beckman Continuous Systolic Monitor. Systolic anddiastolic pressures of three dogs were also obtained with theelectrosphygrnograph cuff attachment to the physiograph, utilizingpressures from both the brachial and tail arteries.

Cardiac output was obtained by the dye-dilution method utilizingCardio-Green dye and a Waters Densitometer. Dye injections were madethrough a catheter inserted through the right jugular vein andpositioned near, or in the right atrium. Arterial sample for dye wasfrom the left carotid artery.

The Shipley-Wilson rotameter was utilized to measure the rate of bloodflow through the femoral artery. Other procedures which were employed toevaluate the effect of the tetrahydroisoquinoline are set forth in theexamples.

Preliminary toxicity studies on2-(3-ethylsulfinylpropyl)-l,2,3,4-tetrahydroisoquinoline were conductedfollowing the usual, well defined, and standardized procedures asdescribed in the phamphlet Appraisal of the Safety of Chemicals inFoods, Drugs and Cosmetics, published in 1959 by the association of Foodand Drug Officials in the United States. (Hogen, Acute Toxicity, page17; Fitzhugh, Sabacute Toxicity, page 26; and Fitzhugh, Chronic OralToxicity, page 36). Sixty day subacute toxicity tests in Wistar rats(15, and 150 mg./l g. of body weight per day) and Beagle dogs (10, 30,and 90 mg./ kg. of body weight per day) indicated no significantbiochemical or histalogical evidence of toxicity. The composition wasadministered to the dogs orally in capsules, once daily, five days perweek. The rats received the same composition orally in drinking waterseven days per Week.

The effective dosage of the compounds of this invention depends upon theindividual characteristics of each case. In general, however, it hasbeen observed that an TABLE II Method Ex. Compound Starting materialExample 242-(3-ethy1thiopropyl)-4-rnethyl-1,2,3,4-tetrahydr0isoquinoline .14-methyl-l,2,3,4-tetrahydroisoquinoline 23 252-(3-ethylsulfinylpropyl)-4-Inetl1yl-1,2,3,4-tetrahydroisoquinoline.Compound of Example 24 23 26. 2-(3-methylth1opropyl)-6-methoxy-1,2,3,1tetrahydroisoquinoline 6-methoxy-1,2,3,4-tetrahydroisoquinoline 23 27.2-(3-methylsulfony1propyl)-6-1nethoxy-1,2,3,4-tetrahydroisoquinolineCompound of Example 26 4 28.2-(3-propylthiopropyl)-7-chloro-1,2,3,4-tctrahydroisoquinolino 232-(3-p1opy1sulfinylpropyl)-7-chloro-1,2,3,4tetrahydroisoquinoline2-(3-ethylthiopropyl)6-trifiuoromethyl-1,2,3,4-t0trahydroisoquiuoline.

2-(3-ethylsulfinylpropyl)-6-trifluoromethyl-1,2,3,4-tetrahydroisoquinolineCompound of Examp 7-chloro-1,2,3,4-tetrahydroisoquinoliucl Compound ofExample 28 4 The manner of using the invention sought to be patented inits process aspect will now be described. Quite unexpectedly, it hasbeen discovered that the tangible embodiments of this invention exhibitfavorable cardiovascular effects in warm blooded animals. It has beenobserved that these compositions are useful as therapeutic agents forincreasing systolic blood pressure, with little or no concurrentincrease in diastolic blood pressure. Hence, the compositions are usefulas valuable therapeutic agents in the alleviation and control of lowsystolic blood pressure as would be associated with shock and otherdisorders. Additionally, it has been observed that the compositions ofthis invention are particularly unique in that while the blood pressureis increased there is no concurrent decrease in blood flow in theperipheral vascular system. In fact, an increase in blood flow rate inthe effective concentration of the tetrahydroisoquinolines will usuallyrange from about 0.10 to about milligrams per kilogram of body weight ofthe warm blooded animal. A preferred range is from about 0.25 to about50 milligrams per kilogram of body weight. The tetrahydroisoquinolinescan be formulated into capsules, tablets, injectable solutions, and thelike. Tablets and capsules can be formulated with the usual ingredientsand excipients such as starch, methylcellulose, natural gums, dibasiccalcium phosphate, lubricants, dispersing agents and the like.

In some instances it may be preferred to administer thetetrahydroisoquinolines by infusion, such as with plasma, at a constantrate over an extended period of time. In such cases, the effectiveconcentration can be adjusted to provide the desired dosage levels.

The following examples set forth the manner of using thetetrahydroisoquinolines of this invention for increasing the bloodpressure in warm blooded animals.

EXAMPLE 32 Effect of tetrahydroisoquinolines on systolic blood pressure(a) An unanesthetized dog having a control blood pressure of 180/70 wasinjected intravenously with 0.5 mg./kg. of2-(3-ethylsulfinylpropy)-1,2,3,4-tetrahydroisoquinoline hydrochlorideand observed for one hour. Immediately following the injection, theperson holding the dog noted a forceful pounding of the heart. This wasaccompanied by an increase in heart rate from a control level of 126 to168. The heart rate then returned to the control level of 126 by the endof thirty minutes. The systolic blood pressure immediately increasedfrom 180 to 220230 and had almost returned to control level by the endof one hour. No increases in diastolic pressure were observed.

(b) A second unanesthetized dog which was very calm and had a controlblood pressure of 120/70 which changed to 150/66 thirty minutes afterintravenous administration of 1 mg./kg. of2-(3-ethylsulfinylpropyl)-1,2,3,4tetrahydroisoquinoline hydrochloride.Heart rate increased from 72 to 100. Little or no gross stimulationoccurred. On another day this same dog was injected intravenously with0.5 mg./kg. of 2-(3-ethylsulfinylpropyl)-1,2,3,4- tetrahydroisoquinolinehydrochloride. From a control pressure of 122/60 the pressure increasedto 130/65 7-10 minutes after injection. A maximal increase to 145/73occurred 43 minutes after injection. One and one-half hours afterinjection the pressure was almost back to control levels.

EXAMPLE 83 Effect of tetrahydroisoquinolines on cardiac output Theeffect of 2-(3-ethylsulfinylpropyl)-1,2,3,4-tetrahydroisoquinoline oncardiac output was determined in a pentobarbitalized dog. The dosage was1 mg./kg. of body weight administered intravenously as thehydrochloride. The cardiac output was obtained by the dyedilution methodutilizing Cardio-Green dye and a Waters Densitometer. Dye injectionswere made through a catheter inserted through the right jugular vein andpositioned near, or in the right atrium. Arterial sampling for dye wasfrom the left carotid artery. The results of this experiment is given inTable III. Each value in the table represents data from one dye-dilutioncurve. The values for controls are averages of the number in parenthesesand were taken during the few minutes immediately precedingadministration of the tetrahydroisoquinoline.

Effect of tetrahydroisoquinolines on blood flow The Shipley-Wilsonrotameter was utilized to measure the rate of blood flow through thefemoral artery in the subject anesthetized dogs. Injection of 1 mg. of2-(3-ethylsulfinylpropyl)-1,2,3,4-tetrahydroisoquinoline hydrochlorideinto the tubing leading directly to the femoral artery resulted in anincrease in flow of 1 to 2 minutes duration. This increased flow wasapparently due to vasodilation since the blood pressure (recorded fromthe same tubing leading directly to the artery) was not increased. Intwo anesthetized dogs femoral blood flow was recorded and 0.5 to 1.0mg./kg. of the same tetrahydroisoquinoline hydrochloride was injectedintravenously. Increases in flow of 3 to 5 minutes duration wereobserved. These changes were not due to any increase in blood pressure.In one of these dogs an additional intravenous injection of 10 mg./ kg.of the tetrahydroisoquinoline caused evidence of prolonged vasodilation.

Simple substituents on the tetrahydroisoquinoline moiety of thecompounds of the present invention do not adversely affect thepharmacological properties thereof, and are to be regarded as the fullequivalents of the compounds of the invention wherein thetetrahydroisoquinoline moiety is unsubstituted. For example, themolecule may also contain substituents wherein R or R groups are otherthan hydrogen. Such additions to the molecular structure of theinventive concept herein described are, therefore, equivalents of thesubject matter sought to be patented.

As previously indicated, the aforementioned general formula defines thecompounds of the present invention as the free base form thereof.Inasmuch as the physical embodiments of the inventive concept havepharmacological utility, for such use the compounds will usually beadministered in the form of their pharmaceutically acceptable acidaddition salts, these salts are the full equivalents of the free baseforms thereof. The acid addition salts can be prepared by reacting thecorresponding free bases in a conventional manner with an inorganic acidsuch as hydrochloric, hydrobrornic, sulfuric and phosphoric; or anorganic acid, such as methanesulfonic, ethanesulfonic, ethanedisulfonic,cyclohexylsulfamic, formic maleic, citric, tartaric and tannic acids.The compounds can also be administered in the form of their quarternaryammonium salts formed by the reaction with a lower alkyl halide.

In addition to their use as the essential active ingredient inpharmaceutical formulations, the novel compositions of this inventioncan be employed in a variety of other fields. For example, thetetrahydroisoquinoline compounds of this invention are useful asintermediates in the synthesis of other chemical compounds.

What is claimed is:

1. A compound selected from the group consisting oftetrahydroisoquinolines having the formula:

wherein A is an alkylene group having at least one and not more thanseven carbon atoms; X is selected from the group consisting of sulfinylor sulfonyl; R is an alkyl group having at least one and not more thanseven carbon atoms; R is selected from the group consisting of hydrogenor lower primary or secondary alkyl groups; R" is selected from thegroup consisting of lower alkyl or lower alkoxy groups; n has a value ofzero through 2; and the pharmaceutically acceptable acid solution saltsof said tetrahydroisoquinolines.

2. The composition of claim 1 wherein R is hydrogen, n is zero and -AX-Ris the alkylsulfinylalkyl group.

3. The composition of claim 1 wherein R is hydrogen, n is zero and A-X-Ris the alkylsulfonylalkyl group.

4. The composition of claim 1 wherein AXR is selected from the groupconsisting of alkylsulfinylpropyl and alkylsulfonylpropyl.

5. The composition of claim 1 wherein R is hydrogen, n is zero and -AXRis the alkylsulfinylpropyl group.

6. The composition of claim 1 wherein R' is hydrogen, n is zero andA-XRis the alkylsulfonylpropyl group.

7. 2 (3-ethylsulffinylpropyl) 1,2,3,4-tetrahydroisoquinoline.

8. 2 (3 ethylsulfonylpropyl) 1,2,3,4 tetrahydroisoquinoline.

References Cited UNITED STATES PATENTS Thirtle 260287X Cusil 260288Bloom 260287X Haack et a1. 260286X 16 Schmidt et al 260283X Yonan 260288Brown 260-247.5

Robinson 260288 5 DONALD G. DAUS, Primary Examiner US. Cl. X.R.

MALL 1790 235 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTIONPatent NO, 3,5R9,61I0 Dated December 22, 1970 Inven r) Allan Poe Gray Itis certified that error appears in the above:l.dentified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column l l, line 57, "R should read --R'--; line 61, "solution" shouldread --addit1on-.

Signed and sealed this 11 th day br May 1971 (SEAL) Attest:

EDWARD M.FLETGHER,JR. WILLIAM E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents

